We studied immunoreactivity for heat shock proteins (HSPs) in multiple sclerosis (MS) brain tissue and detected HSP-65 in chronic MS plaques at the edge of thinly myelinated (or remyelinated) areas. Serial-section immunocytochemistry and double staining revealed that HSP-65+ cells represented reactive, immature oligodendrocytes with strong reactivity for myelin basic protein and weak reactivity for galactocerebroside. Mature oligodendrocytes outside MS plaques did not stain for HSP-65. Control brain sections showed no HSP-65 reactivity. Oligodendrocytes expressed HSP-65 in mixed glial cell cultures. In this system in vitro, oligodendrocytes, but not astrocytes, showed constitutive expression of HSP-65. There was immunoreactivity for HSP-72 in astrocytes in MS and non-MS brains to a similar extent but no association between HSP-72 reactivity and MS plaques. Interestingly, HSP-65+ oligodendrocytes colocalized with T lymphocytes expressing the gamma delta T-cell receptor (TcR). Since HSP-65 has been implicated as a major antigen recognized by TcR gamma delta lymphocytes, our findings might represent a new immunologic interaction within MS plaques that leads to the destruction of immature oligodendrocytes involved in remyelination.